population expansion

Fu W, O'Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, Gabriel S, Altshuler D, Shendure J, Nickerson DA, Bamshad MJ, NHLBI Exome Sequencing Project & Akey SM 2013 Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493:216-220.

  • we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs)
  • approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years
  • European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal
  • we estimated the age of all 1,146,401 SNVs using 6 different demographic models5,6,8-11, 3 of which considered recent explosive population growth5,6,8
  • estimates of allele age were generally robust across different demographic models
  • accordingly, we report results based on a modified Out-of-Africa model9 in which accelerated population growth began 5,115 years ago with a per-generation growth rate of 1.95% and 1.66% for European Americans and African Americans, respectively6
  • we observed an SNV approximately once every 52 base pairs (bp) and 57 bp in European Americans and African Americans
  • the European American and African American samples contain approximately fivefold and threefold increases in SNVs, respectively, attributable to explosive population growth, resulting in a large burden of rare SNVs predicted to have arisen very recently
  • 73.2% of SNVs (81.4% and 58.7% in European Americans and African Americans, respectively) are predicted to have arisen in the past 5,000 years
  • SNVs that arose more than 50,000 years ago were observed more frequently in the African American samples (Fig. 1b), which probably reflects stronger genetic drift in European Americans associated with the Out-of-Africa dispersal
  • the bottleneck associated with the Out-of-Africa dispersal led to less efficient purging of weakly deleterious alleles
  • the spectrum of protein-coding variation is considerably different today compared to what existed as recently as 200 to 400 generations ago
  • rare variants have an important role in heritable phenotypic variation, disease susceptibility and adverse drug responses
  • the recent dramatic increase in human population size, resulting in a deluge of rare functionally important variation, has important implications for understanding and predicting current and future patterns of human disease and evolution
  • the increased mutational capacity of recent human populations has led to a larger burden of Mendelian disorders, increased the allelic and genetic heterogeneity of traits, and may have created a new repository of recently arisen advantageous alleles that adaptive evolution will act upon in subsequent generations